WO1997002830A2 - Use of indigestible oligosaccharides to treat and prevent otitis media in humans - Google Patents

Use of indigestible oligosaccharides to treat and prevent otitis media in humans Download PDF

Info

Publication number
WO1997002830A2
WO1997002830A2 PCT/US1996/011243 US9611243W WO9702830A2 WO 1997002830 A2 WO1997002830 A2 WO 1997002830A2 US 9611243 W US9611243 W US 9611243W WO 9702830 A2 WO9702830 A2 WO 9702830A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
otitis media
human
indigestible oligosaccharide
indigestible
Prior art date
Application number
PCT/US1996/011243
Other languages
French (fr)
Other versions
WO1997002830A3 (en
Inventor
Margaret Ione Halpin Dohnalek
Karin Margaret Ostrom
Milo Duane Hilty
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU63452/96A priority Critical patent/AU719547B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to DK96922652T priority patent/DK0837686T3/en
Priority to NZ312022A priority patent/NZ312022A/en
Priority to DE69624243T priority patent/DE69624243T2/en
Priority to JP50587997A priority patent/JP2002502357A/en
Priority to BR9609619A priority patent/BR9609619A/en
Priority to IL12273596A priority patent/IL122735A0/en
Priority to MX9800331A priority patent/MX9800331A/en
Priority to EP96922652A priority patent/EP0837686B1/en
Priority to AT96922652T priority patent/ATE225662T1/en
Publication of WO1997002830A2 publication Critical patent/WO1997002830A2/en
Publication of WO1997002830A3 publication Critical patent/WO1997002830A3/en
Priority to NO980071A priority patent/NO980071L/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/36—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
    • A23G3/364—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G3/368—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/20—Dietetic milk products not covered by groups A23C9/12 - A23C9/18
    • A23C9/203—Dietetic milk products not covered by groups A23C9/12 - A23C9/18 containing bifidus-active substances, e.g. lactulose; containing oligosaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a method for reducing the incidence of otitis
  • Fructooligosaccharides are natural substances composed primarily of
  • fructose molecules They belong to a group of carbohydrates that occur in many
  • FOS are indigestible oligosaccharides that pass through the small
  • FOS can be utilized efficiently by lactobacilli
  • Indigestible oligosaccharides refers to a small carbohydrate moiety that is
  • Fructooligosaccharides are indigestible oligosaccharides that are members of
  • FOS the inulin subclass of fructosans, polymers composed of fructose residues.
  • the tetramer nystose is composed of three fructose monomers bound to glucose (or sucrose plus two fructose units) and has a DP of 3.
  • sucrose is GF- (glucose plus fructose).
  • inulins are the following hormones: glutamate, glutamate, glutamate, glutamate, glutamate, glutamate, glutamate
  • glucofructosans carbohydrate polymers consisting of a chain of fructose residues
  • Fructooligosaccharides can be produced enzymatically, through
  • FOS occur in nature in
  • FOS FOS
  • sucrose nytrose or GF 3 in which two molecules of fructose are bound to sucrose;
  • fructosyltransferase could be a fungus such as Aspergillus niger.
  • Richards U.S. Patent No. 5,318,794 discloses a method for producing a
  • the method comprises heating sucrose
  • fructose oligosaccharides are formed.
  • This method produces a mixture of oligosaccharides, many of which differ in structure from the GF 2 , GF 3 ,
  • WO 94/27618 provides examples of infants and adults suffering
  • the present invention is, by:
  • the human consumes 1.0 to 4.0 grams per day and in yet a still more
  • the human consumes 1.5 to 3.5 grams per day of FOS.
  • neosugar genotoxicity, carcinogenicity, and chronic toxicity
  • FOS is used in Japan in many
  • said method comprising enterally administering an effective amount of
  • This invention more specifically relates
  • said method comprises enterally administering from 0.5 grams to 5 grams per day of an indigestible oligosaccharide.
  • the indigestible oligosaccharides useful in this invention are selected from
  • fructooligosaccharides fhictosans, xylooligosaccharides and galactooligosaccharides.
  • the fructooligosaccharides are selected from 1-kestose, nystose and l F - ⁇ -fructofuranosyl nystose.
  • the indigestible oligosaccharides are
  • the indigestible oligosaccharides are contained in a nutritional product such as infant
  • Enteral administration ofthe indigestible oligosaccharides can also be accomplished through their inclusion in products such as infant formula, 'follow-on'
  • fermented products candies, tablets, chewing gums, lozenges, yogurts, fermented products and the like.
  • fermented products means products such as cottage cheese or fermented milk that use specified cultures of microorganisms in their manufacture. It has been
  • the study beverages were the sole source of milk fed to the children during the period
  • indigestible oligosaccharides refers to
  • substrate for fermentation by selected bacteria like lactobacilli and bifidobacteria
  • Indigestible oligosaccharides that may be employed in the preferred embodiments of the invention may be prepared enzymatically, by chemical means or extracted from
  • effective amount ofthe indigestible oligosaccharide can range from 0.5 - 5 grams per day.
  • Sucrose GFr m The structure ofthe general form is shown as GF n , and the fructosan molecule is
  • F m Any molecule depicted as GF n or F m can be used in the practice ofthe
  • indigestible oligosaccharides such as xylooligosaccharides and
  • galactooligosaccharides will have a degree of polymerization ranging from 2 to 20.
  • Xylooligosaccharides selected from the group consisting of xylobiose, xylotriose and
  • xylotetrose are useful in the present invention.
  • the invention relates to a method of reducing the incidence of otitis media in a human, said method comprising enterally administering a therapeutically
  • oligosaccharide is selected from the group consisting of fructooligosaccharides, fhictosans, xylooligosaccharides and galactooligosaccharides having a degree of
  • the FOS used in the clinical study was obtained from Golden
  • Carbohydrate composition (% dry basis)
  • the Fructooligosaccharides Powder was a white powder with a granular size of less than 42 mesh. This FOS was used to prepare the milk-based fortified infant formula substantially in accordance with U.S. Patent 5,021,245, the teachings of which
  • sucrose and 166 lbs. of FOS were dissolved in water. This carbohydrate solution was
  • Control was designated as Control; the same milk-based beverage that served as the Control formula was supplemented with FOS at 3.5 grams per liter and was designated as Experimental. Milk beverages other than the child's assigned study
  • the study beverages were powder products that were reconstituted with water
  • the powdered Control and Experimental beverages were reconstituted by mixing 135 grams of powdered nutritional with 1 liter of water.
  • the beverages contained approximately 670 to 725 Kcal per L.
  • the powdered products were provided in clinically labeled 400 gram cans.
  • the beverage was a modified, fortified milk-based drink with or without FOS that met
  • Linolenic Acid mg. 6500 6500
  • Vitamin A IU 2900 2900
  • Vitamin D IU 440 440
  • Vitamin K meg 112 112
  • Vitamin B 12 meg 3.24 3.24
  • Pantothenic Acid meg 4250 4250
  • Vitamin C Ascorbic Acid
  • mg 150 Vitamin C
  • Day care center records and clinic or physician visits were monitored for clinically significant illnesses, such as diarrhea, bronchitis, bronchiolitis, and otitis media.
  • Research nurses and physicians reviewed day care center records and clinic or physician records to document illnesses.
  • the number of children with otitis media and the number of episodes of otitis media in each feeding group were analyzed by the Cox regression analysis, using the marginal approach to multivariate survival analysis.
  • the analysis ofthe number of episodes of otitis media counts all episodes including repeated episodes.
  • Indigestible oligosaccharides can be added to various nutritional products including but not limited to infant formula and products for older children and adults, such as 'follow-on' formulas and toddler's beverages and also milk and yogurt products. They can be formulated in candies, tablets, lozenges, chewing gums and also mixed into dietary supplements and other liquid and powdered foods.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

A method is provided for reducing the incidence of otitis media in infants and young children by enterally administering indigestible oligosaccharides. More specifically, the present invention relates to a method for reducing the incidence of otitis media comprising administering to humans an indigestible oligosaccharide selected from the group consisting of fructooligosaccharides, fructosans, xylooligosaccharides and galactooligosaccharides. The indigestible oligosaccharides can be produced through enzymatic synthesis, chemical techniques or isolated from plant materials and are administered in the form of a nutritional product, candy, tablets, chewing gums, lozenges, milk products, yogurts and the like. In a preferred embodiment of this invention, the indigestible oligosaccharides have a DP of 2 to 20 and still more preferably are the fructooligosaccharides GF2, GF3 and GF4.

Description

USE OF INDIGESTIBLE OLIGOSACCHARIDES TO TREAT AND PREVENT OTmS MEDIA IN HUMANS
This application claims the benefit of U.S. Provisional Application No. 60/001 ,000 filed July 10, 1995.
FIELD OF THE INVENTION
The present invention relates to a method for reducing the incidence of otitis
media by enterally administering to humans an indigestible oligosaccharide.
BACKGROUND OF THE INVENTION Prevention of otitis media in young children is a significant public health
problem that has not been solved. Methods of prevention presently available are
limited to practices that reduce transmission of infectious agents to susceptible individuals. Such methods include provision of clean water, hand washing, and good personal hygiene. The development of effective vaccines to prevent otitis media has
been limited because ofthe large number of potential pathogens that can cause this
disease and because young children, who are at greatest risk, often fail to develop
effective immunity. Individuals treated with antibiotics for otitis media and other infectious diseases may become colonized with antibiotic-resistant bacteria and may not respond to antibiotic treatment.
Fructooligosaccharides (FOS) are natural substances composed primarily of
fructose molecules. They belong to a group of carbohydrates that occur in many
different plants. FOS are indigestible oligosaccharides that pass through the small
intestine without being digested, reaching the large intestine where they are selectively fermented by certain microorganisms. FOS can be utilized efficiently by lactobacilli
and bifidobacteria, species of bacteria that are beneficial for human health (Hidaka et
al). Selective fermentation of FOS by bifidobacteria leads to an increase in the
presence of these bacteria and to the production of acetic acid and lactic acid as
fermentation endproducts, resulting in a lower pH in the digestive tract and providing a
means to prevent the overgrowth of harmful bacteria like Escherichia coli, Clostridium
perfringens and Clostridium difficile. (Hidaka et al., "Fructooligosaccharides:
Enzymatic Preparation and Biofunctions", Journal of Carbohydrate Chemistry 10(4):
509-522, 1991).
Indigestible Oligosaccharides
"Indigestible oligosaccharides" refers to a small carbohydrate moiety that is
resistant to endogenous digestion in the human upper digestive tract.
Fructooligosaccharides (FOS) are indigestible oligosaccharides that are members of
the inulin subclass of fructosans, polymers composed of fructose residues. FOS are
sometimes characterized by their degree of polymerization. Degree of Polymerization
(DP) means the number of covalent bonds between the monosaccharide units in the
polymer. For example, the tetramer nystose is composed of three fructose monomers bound to glucose (or sucrose plus two fructose units) and has a DP of 3. Using this
nomenclature, sucrose is GF- (glucose plus fructose). Specifically, inulins are
glucofructosans, carbohydrate polymers consisting of a chain of fructose residues
linked by (2→l)-β-glycosidic bonds and usually having a single D-glycosyl residue
linked (\→2)-a- to the first fructose molecule. Fructooligosaccharides (FOS) can be produced enzymatically, through
chemical techniques or by extraction from natural substances. FOS occur in nature in
many kinds of plants, including onions, garlic, shallots, artichokes, wheat, rye,
bananas, asparagus and tomatoes, that are commonly part of a human diet (Speights et
al., "Fructooligosaccharides- A Low Caloric Bulking Agent- And More From Sucrose",
Carbohydrates in Industrial Synthesis, ed. M.A. Clarke, Proceedings ofthe
Symposium ofthe Division of Carbohydrate Chemistry ofthe American Chemical
Society, 1992). Another natural source of FOS is the chicory root. FOS can also be
synthesized from sucrose through the use of transfructosy lating enzymes. Treatment of 50% (w/v) sucrose with the transfructosylating enzyme from Aspergillus niger results in a mixture of fructooligosaccharides containing 2,3, or 4 fructose residues,
designated respectively: 1-kestose or GF2 in which one molecule of fructose is bound
to sucrose; nytrose or GF3 in which two molecules of fructose are bound to sucrose;
and lF-β-fructofuranosyl nystose or GF4 in which three molecules of fructose are
bound to sucrose.
An enzymatic method of producing FOS industrially is disclosed in U.S. Patent No. 4,681,771 to Adachi et al. that comprises reacting sucrose in the presence of a fructosyltransferase (enzyme) to obtain GF2, GF3, GF4, and GF5. The source for the
enzyme, fructosyltransferase, could be a fungus such as Aspergillus niger.
Richards (U.S. Patent No. 5,318,794) discloses a method for producing a
product (caramel) containing between 20 and 50% fructose oligosaccharides, having a degree of polymerization (DP) of about 3-10. The method comprises heating sucrose
and an organic acid until fructose oligosaccharides are formed. This method produces a mixture of oligosaccharides, many of which differ in structure from the GF2, GF3,
and GF4used in the present invention.
Richards et al. (WO 94/27618) disclosed a method for the treatment and
prevention of diarrhea comprising administration of a caramel prepared according either to the process of U.S. Patent No. 5,318,794 or according to the process of U.S.
Patent No. 5,206,355. WO 94/27618 provides examples of infants and adults suffering
from diarrhea who were treated with the caramels. The present invention is, by
contrast, directed to the prevention of otitis media in children by prophylactic administration of fructooligosaccharides.
Analysis of human breast milk has determined that it does not contain the FOS
of this invention. Kunz and Rudloff have reported in an article entitled "Biological
functions of oligosaccharides in human milk" Acta Paediatr. 82:903-12 (1993) that the
monomers of breast milk oligosaccharides are D-glucose, D-galactose, N-
acetylglucosamine, L-fucose and sialic acid. With few exceptions, all ofthe breast milk oligosaccharides carry lactose at their reducing end. In contrast, the present
inventors have discovered that the very different fructooligosaccharides (FOS) with a
degree of polymerization of from 2 to 20 can reduce the manifestation of otitis media
in a human consuming from 0.5 to 5 grams per day FOS. In a more preferred
embodiment, the human consumes 1.0 to 4.0 grams per day and in yet a still more
preferred embodiment, the human consumes 1.5 to 3.5 grams per day of FOS.
Animal toxicology studies have shown no evidence of toxicity, mutagenicity,
or carcinogenic effects due to FOS (Clevenger et al., "Toxicological evaluation of
neosugar: genotoxicity, carcinogenicity, and chronic toxicity", Journal ofthe American College of Toxicology 7:643-662, 1988). FOS is used in Japan in many
food products and has been added to infant formula. (Fructooligosaccharide
Information Package, Coors BioTech, Inc. May 1990).
SUMMARY OF THE INVENTION
There is disclosed, a method of reducing the incidence of otitis media in a
human, said method comprising enterally administering an effective amount of
indigestible oligosaccharides to said human. This invention more specifically relates
to a method of preventing otitis media in a human, said method comprises enterally administering from 0.5 grams to 5 grams per day of an indigestible oligosaccharide. The indigestible oligosaccharides useful in this invention are selected from
fructooligosaccharides, fhictosans, xylooligosaccharides and galactooligosaccharides.
In a preferred embodiment, the fructooligosaccharides are selected from 1-kestose, nystose and lF-β-fructofuranosyl nystose. The indigestible oligosaccharides are
administered enterally in any convenient form. In one embodiment ofthe invention, the indigestible oligosaccharides are contained in a nutritional product such as infant
formula. Enteral administration ofthe indigestible oligosaccharides can also be accomplished through their inclusion in products such as infant formula, 'follow-on'
formula, toddler's beverages, milk, dietary supplements, fruit juice, fruit based drinks,
candies, tablets, chewing gums, lozenges, yogurts, fermented products and the like. The term "fermented products" means products such as cottage cheese or fermented milk that use specified cultures of microorganisms in their manufacture. It has been
found that administration of from 0.5 to 5 grams per day ofthe indigestible oligosaccharides will be efficacious in reducing the incidence of otitis media in a
human.
In order to demonstrate the present invention a clinical study was undertaken to
test whether the enteral administration of FOS would reduce the incidence of otitis
media. A controlled 16 week, randomized blinded study was undertaken to determine
if feeding indigestible oligosaccharides or fructooligosaccharides would reduce the
incidence of otitis media in young children attending day care centers. Children were
enrolled in the study and fed one of two study beverages: a milk-based beverage that served as a control or the same milk-based beverage containing FOS (Experimental).
The study beverages were the sole source of milk fed to the children during the period
ofthe study. The subjects were placed on active surveillance for illnesses including otitis media upon enrollment into the study. Results ofthe study show that the incidence of otitis media in subjects consuming FOS was significantly lower than in subjects consuming the control beverage.
DETAILED DESCRIPTION OF THE INVENTION
As used herein and in the claims "indigestible oligosaccharides" refers to
carbohydrates with a degree of polymerization of from 2 to 20 (GF - GF20)and/or a
molecular weight less than about 3,600 that is resistant to endogenous digestion in the human upper digestive tract. These "indigestible oligosaccharides" are utilized as a
substrate for fermentation by selected bacteria like lactobacilli and bifidobacteria
species and other nonpathogenic bacteria that reside in the lower gastrointestinal tract.
Indigestible oligosaccharides that may be employed in the preferred embodiments of the invention may be prepared enzymatically, by chemical means or extracted from
natural substances. As used herein and in the claims, effective amount ofthe indigestible oligosaccharide can range from 0.5 - 5 grams per day.
Chemical structures of sucrose and some fructooligosaccharides useful in the
practice ofthe present invention are shown below.
Figure imgf000009_0001
Sucrose GFr m The structure ofthe general form is shown as GFn, and the fructosan molecule is
designated Fm. Any molecule depicted as GFn or Fm can be used in the practice ofthe
present invention. These include in the preferred embodiment 1-kestose (GF2 in which
one molecule of fructose is bound to sucrose), nystose (GF3 in which two molecules of
fructose are bound to sucrose), and lF-β-fructofuranosyl nystose (GF4 in which three
molecules of fructose are bound to sucrose). In other embodiments ofthe invention
indigestible oligosaccharides such as xylooligosaccharides and
galactooligosaccharides will have a degree of polymerization ranging from 2 to 20.
Xylooligosaccharides selected from the group consisting of xylobiose, xylotriose and
xylotetrose are useful in the present invention. Xylooligosaccharides and
galactooligosaccharides [(Galactose)n-Galactose-Glucose] wherein N can range from 1
to 10 are also useful in the present invention.
In general, the invention relates to a method of reducing the incidence of otitis media in a human, said method comprising enterally administering a therapeutically
effective amount of an indigestible oligosaccharide to said human. The indigestible
oligosaccharide is selected from the group consisting of fructooligosaccharides, fhictosans, xylooligosaccharides and galactooligosaccharides having a degree of
polymerization of 2 to 20.
METHODS AND MATERIALS
The indigestible oligosaccharides used in the clinical study were synthesized
according to the method disclosed in U.S. 4,681,771 to Adachi et al. The teachings of
U.S. 4,681,771 are incorporated herein by reference. The process comprises reacting sucrose in the presence of a fructosyltransferase from Aspergillus niger to obtain GF2,
GF3, and GF4. The FOS used in the clinical study was obtained from Golden
Technologies, Inc. of Westminster, CO. The Fructooligosaccharides Powder was Lot
No. 931115 and had the following chemical analysis:
Moisture - 2.5
Carbohydrate composition (% dry basis)
Glucose and Fructose - 0.5
Sucrose - 3.5
FOS - 96.0 GF2 - 41.3
GF3 - 45.7
GF4 - 9.0
The Fructooligosaccharides Powder was a white powder with a granular size of less than 42 mesh. This FOS was used to prepare the milk-based fortified infant formula substantially in accordance with U.S. Patent 5,021,245, the teachings of which
are herein incorporated by reference. More specifically, to produce a 5,700 lb. batch
ofthe powdered Experimental formula, a mixture of 20 lbs. of lactose, 1,100 lbs. of
sucrose and 166 lbs. of FOS were dissolved in water. This carbohydrate solution was
then combined with the protein, oils and vitamins set forth in Table 1 , heat processed, homogenized, spray dried and packaged into containers.
Study Design
A controlled, blinded, randomized 16 week study was conducted on children
attending day care centers. Children between 10 and 24 months of age were enrolled
in the study and fed one of two beverages: a milk-based beverage that served as the
control and was designated as Control; the same milk-based beverage that served as the Control formula was supplemented with FOS at 3.5 grams per liter and was designated as Experimental. Milk beverages other than the child's assigned study
beverage were restricted. The study beverages were fed ad libitum as the sole source
of milk.
At entry into the study, children were placed under active surveillance for otitis media and other significant medical illnesses. Surveillance included study evaluations
at days 7, 28, 56, 84 and 112. Research nurses visited the participating day care
centers each week to ensure study compliance and identify illness episodes.
Study Diet
The study beverages were powder products that were reconstituted with water
at the point of consumption. The powdered Control and Experimental beverages were reconstituted by mixing 135 grams of powdered nutritional with 1 liter of water. The beverages contained approximately 670 to 725 Kcal per L.
The powdered products were provided in clinically labeled 400 gram cans.
The beverage was a modified, fortified milk-based drink with or without FOS that met
the nutrient levels recommended by the Committee on Nutrition of the American
Academy of Pediatrics as required by the Infant Formula Act of 1980. The study
beverage compositions are shown in Table 1.
Both beverages provided 20 calories per fluid ounce when reconstituted with water. The average daily intake for children receiving Control beverage was 750 mL
and for children receiving Experimental beverage was 766 mL which resulted in
consumption of approximately 2.6 grams of FOS per day. TABLE 1
PRODUCT COMPOSITION
Approximate Composition of Study Beverage
With or Without Fructooligosaccharides (per liter)
Experimental Study Beverage with
NUTRIENT Fructool i gosaccharides Control Studv Beverage
Protein, g 15.3 15.3
Fat, g 37.2 37.2
Carbohydrate, g 74.7 74.7
Linolenic Acid, mg. 6500 6500
Vitamin A, IU 2900 2900
Vitamin D, IU 440 440
Vitamin K, meg 112 112
Thiamine (B,), meg 239 239
Riboflavin (B2), meg 1505 1505
Vitamin B12, meg 3.24 3.24
Niacin, meg 9000 9000
Folic Acid (Folacin), meg 155 155
Pantothenic Acid, meg 4250 4250
Biotin, meg 45.0 45.0
Vitamin C (Ascorbic Acid), mg 150 150
Choline, mg 156 156
Inositol, mg 38 38
Calcium, mg 975 975
Phosphorus, mg 650 650
Magnesium, mg 75 75
Iron, mg 13 13 •
Zinc, mg 8.5 8.5
Manganese, meg 52 52
Copper, meg 710 710 Sodium, mg 220 220
Iodine, meg 46 46
Potassium, mg 840 840
Chloride, mg 620 620
Taurine, mg 57.5 57.5
Energy (Kcal) 684 684 β-Carotene, meg 400 400
% Kcal from protein 8.95 8.95
Nucleotides, mg 72 72
FOS 3.5 0
Study Subjects and Entry Procedures
Children were randomly assigned to receive Experimental or Control. The children were in apparent good health with no history of aspiration pneumonia, chronic gastroenteritis or diarrhea within seven days prior to enrollment. Subjects were prohibited from receiving human milk feedings for the duration ofthe study and had a history of ingesting whole cow's milk or cow's milk-based formula.
Day care center records and clinic or physician visits were monitored for clinically significant illnesses, such as diarrhea, bronchitis, bronchiolitis, and otitis media. Research nurses and physicians reviewed day care center records and clinic or physician records to document illnesses.
Statistical Methods
The number of children with otitis media and the number of episodes of otitis media in each feeding group were analyzed by the Cox regression analysis, using the marginal approach to multivariate survival analysis. The analysis ofthe number of episodes of otitis media counts all episodes including repeated episodes. Incidence of Otitis Media
The incidence of otitis media in subjects consuming the experimental beverage containing FOS was significantly lower than in subjects consuming the Control beverage. Fifty subjects had documented episodes of otitis media during the course of the study: 17 of the 131 subjects receiving the Experimental beverage and 32 ofthe 134 subjects receiving Control. This is statistically significant with a probability of p = 0.023. Results are summarized in Table 2.
Table 2 OTITIS MEDIA EPISODES
EXPERIMENTAL CONTROL BEVERAGE BEVERAGE
N=131 N=134
NUMBER OF CHILDREN HAVING OTITIS MEDIA* 17 33
REPEAT EPISODES OF HAVING OTITIS MEDIA 9 18
TOTAL NUMBER OF EPISODES OF OTITIS MEDIA** 26 51
*p = 0.023 by Cox Regression Analysis **p = 0.0486 by Multivariant Cox Regression Analysis
It is concluded from the results ofthe clinical study that administration of an indigestible oligosaccharide such as FOS reduces the incidence of otitis media in children. The reduced incidence of otitis media seen in the group of children fed FOS was unexpected. The prior art does not suggest or disclose that enteral administration of FOS would be effective in preventing the incidence of otitis media.
According to the present invention, it has been discovered that sugars selected from the indigestible oligosaccharides, particularly fructooligosaccharides can prevent the occurrence of otitis media. The present invention provides a method for reducing the incidence of otitis media. Indigestible oligosaccharides can be added to various nutritional products including but not limited to infant formula and products for older children and adults, such as 'follow-on' formulas and toddler's beverages and also milk and yogurt products. They can be formulated in candies, tablets, lozenges, chewing gums and also mixed into dietary supplements and other liquid and powdered foods.
Industrial Applicability
The occurrence of otitis media is a major healthcare problem. The medical community has few tools to prevent and treat this disease, therefore the present invention will fulfill a long felt need. It is suφrising that the enteral administration of naturally occurring indigestible oligosaccharides or sugars would be effective in reducing otitis media in humans.
While various embodiments ofthe present invention have been described in detail, it will be apparent to those skilled in the art that modifications and adaptations will occur to those skilled in the art. However, it is to be expressly understood that such modifications and adaptations are within the scope ofthe present invention, as set forth in the following claims.

Claims

What is claimed is:
1. A method of reducing the incidence of otitis media in a human said method comprising enterally administering an effective amount of an indigestible oligosaccharide to said human.
2. The method of claim 1, wherein said indigestible oligosaccharide is selected from the group consisting of fructooligosaccharides, fhictosans, xylooligosaccharides and galactooligosaccharides.
3. The method of claim 2, wherein the fructooligosaccharide is selected from the group consisting of 1-kestose, nystose, and lF-β-fructofuranosyl nystose.
4. The method of claim 1, wherein the indigestible oligosaccharide is administered in a nutritional product.
5. The method of claim 4, wherein the nutritional product is selected from the group consisting of an infant formula, follow-on formula, toddler's beverage, milk, yogurts, fermented products and dietary supplements.
6. The method of claim 4, wherein the nutritional product is selected from the group consisting of fruit juice and fruit-based drinks.
7. The method of claim 1, wherein the indigestible oligosaccharide is administered in a candy, a tablet, a chewing gum, a lozenge or a liquid.
8. The method of claim 1 , wherein the indigestible oligosaccharide is administered at a rate of at least 0.5 grams per day to 5 grams per day.
9. The method of claim 3 wherein the nutritional product is selected from the group consisting of yogurts and fermented products.
10. A method of preventing otitis media in a human, said method comprising enterally administering to said human from 0.5 to 5 grams per day of at least one indigestible oligosaccharide selected from the group of oligosaccharides having a degree of polymerization of from 2 to 20.
11. A method according to claim 10 wherein said indigestible oligosaccharide is selected from the group consisting of fructooligosaccharides, fructosans, xylooligosaccharides and galactooligosaccharides.
12. A method according to claim 11 wherein the fructooligosaccharide is selected from the group consisting of 1-kestose, nystose, and l-F-β-fructofuranosyl nystose.
13. A method according to claim 10 wherein the indigestible oligosaccharide is administered in a nutritional product.
14. A method according to claim 13 wherein the nutritional product is selected from the group consisting of an infant formula, follow-on formula, toddler's beverage, milk, yogurts, fermented products and dietary supplements.
15. A method according to claim 13 wherein the nutritional product is selected from the group consisting of fruit juice and fruit based drinks.
16. A method according to claims 10 wherein the indigestible oligosaccharide is administered in a candy, a chewing gum, a tablet, a lozenge or a liquid.
17. A method for reducing the occurrence of otitis media in a human, said method comprises enterally administering to said human at least 1 gram per day of at least one fructooligosaccharide selected from the group consisting of GF2, GF3 and GF4.
PCT/US1996/011243 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans WO1997002830A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
BR9609619A BR9609619A (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans
DK96922652T DK0837686T3 (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides for the treatment and prevention of otitis media in humans
NZ312022A NZ312022A (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans
DE69624243T DE69624243T2 (en) 1995-07-10 1996-07-02 USE OF INDIGESTIBLE OLIGOSACCHARIDES FOR THE PREVENTION AND TREATMENT OF MEDIUM-EARTH IGNITION IN PEOPLE
JP50587997A JP2002502357A (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides for the treatment and prevention of human otitis media
AU63452/96A AU719547B2 (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans
IL12273596A IL122735A0 (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans
AT96922652T ATE225662T1 (en) 1995-07-10 1996-07-02 USE OF INDIGESTIBLE OLIGOSACCHARIDES FOR PREVENTING AND TREATING MEDICINE EAR INFLAMMATION IN HUMAN BEINGS
EP96922652A EP0837686B1 (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans
MX9800331A MX9800331A (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans.
NO980071A NO980071L (en) 1995-07-10 1998-01-07 Use of indigestible oligosaccharides to treat and prevent otitis media in humans

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US100095P 1995-07-10 1995-07-10
US08/653,083 1996-06-11
US60/001,000 1996-06-11
US08/653,083 US5849324A (en) 1995-07-10 1996-06-12 Use of indigestible oligosaccharides to reduce the incidence of otitis media in humans

Publications (2)

Publication Number Publication Date
WO1997002830A2 true WO1997002830A2 (en) 1997-01-30
WO1997002830A3 WO1997002830A3 (en) 1997-04-10

Family

ID=26668400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/011243 WO1997002830A2 (en) 1995-07-10 1996-07-02 Use of indigestible oligosaccharides to treat and prevent otitis media in humans

Country Status (17)

Country Link
US (1) US5849324A (en)
EP (1) EP0837686B1 (en)
JP (1) JP2002502357A (en)
AR (1) AR002771A1 (en)
AT (1) ATE225662T1 (en)
AU (1) AU719547B2 (en)
BR (1) BR9609619A (en)
CA (1) CA2226420A1 (en)
DE (1) DE69624243T2 (en)
DK (1) DK0837686T3 (en)
ES (1) ES2186788T3 (en)
IL (1) IL122735A0 (en)
MX (1) MX9800331A (en)
NO (1) NO980071L (en)
NZ (1) NZ312022A (en)
PT (1) PT837686E (en)
WO (1) WO1997002830A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0951844A2 (en) * 1998-04-22 1999-10-27 Hans-Günter Berner Energy-drink based on fruit juices
WO2000030477A1 (en) * 1998-11-19 2000-06-02 Norbert Fuchs Beverage for increasing the body's capacity to break down alcohol
WO2001060346A2 (en) * 2000-02-17 2001-08-23 Wyeth Nutritional formulation containing prebiotic substances
US6630452B2 (en) 2000-02-17 2003-10-07 Wyeth Nutritional formulation containing prebiotic substances

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19701382A1 (en) * 1997-01-16 1998-07-23 Nutricia Nv Carbohydrate mix
US8642051B2 (en) 2000-03-21 2014-02-04 Suzanne Jaffe Stillman Method of hydration; infusion packet system(s), support member(s), delivery system(s), and method(s); with business model(s) and Method(s)
EP1243273A1 (en) * 2001-03-22 2002-09-25 Societe Des Produits Nestle S.A. Composition comprising a prebiotic for decreasing infammatory process and abnormal activation of non-specific immune parameters
PL375071A1 (en) * 2002-10-11 2005-11-14 Wyeth Nutritional formulations containing synbiotic substances
US7951410B2 (en) * 2003-04-14 2011-05-31 Mead Johnson Nutrition Company Enteral compositions containing caseinoglycomacropeptide having an enhanced concentration of sialic acid
US7867541B2 (en) * 2003-04-14 2011-01-11 Mead Johnson Nutrition Company Compositions and methods of formulation for enteral formulas containing sialic acid
AU2004324720B2 (en) * 2004-11-12 2011-10-27 N.V. Nutricia Liquid transition nutrition for infants
FR2894827B1 (en) * 2005-12-21 2010-10-29 Galderma Res & Dev PHARMACEUTICAL OR COSMETIC PREPARATIONS FOR TOPICAL AND / OR PARENTERAL APPLICATION, PROCESSES FOR THEIR PREPARATION, AND USES THEREOF
EP1886680A1 (en) * 2006-05-23 2008-02-13 Nestec S.A. Maternal supplement
US20090297660A1 (en) * 2008-06-02 2009-12-03 Kraft Food Holdings, Inc. Cheese Products Containing Galacto-Oligosaccharides And Having Reduced Lactose Levels
US9392814B2 (en) 2014-06-06 2016-07-19 Nicholas J. Singer Delivery system for drinks
USD773313S1 (en) 2015-06-23 2016-12-06 Nicholas J. Singer Package
US9907323B2 (en) 2015-09-25 2018-03-06 Mead Johnson Nutrition Co. Infant formula tablets

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB978170A (en) * 1961-08-04 1964-12-16 Koninklijke Gist Spiritus Process for the preparation of water-soluble derivatives of polyene antibiotics

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2072679B (en) * 1980-03-31 1983-11-09 Meiji Seika Kaisha Sweetener
US4859488A (en) * 1987-09-15 1989-08-22 Kabushiki Kaisha Yakult Honsha Liquid food for curing constipation: polydextrose and oligosaccharide
JPH02178229A (en) * 1988-12-28 1990-07-11 Fujirebio Inc Antiviral agent
US5219842A (en) * 1989-08-29 1993-06-15 Nihon Shokuhin Kako Co., Ltd. Method of improving intestinal floras
US5021245A (en) * 1990-05-22 1991-06-04 Abbott Laboratories Infant formula containing a soy polysaccharide fiber source
US5206355A (en) * 1991-09-30 1993-04-27 The University Of Montana Preparation of trisaccharides (kestoses) and polymers by pyrolysis of amorphous sucrose
JP2654529B2 (en) * 1992-03-27 1997-09-17 大塚製薬株式会社 Health drink composition
US5318794A (en) * 1992-12-02 1994-06-07 The University Of Montana Process for producing caramel having a high content of fructose oligosaccharides and caramel product produced thereby
US5439893A (en) * 1993-05-26 1995-08-08 University Of Montana Methods for the treatment and prevention of diarrhea
JPH0725772A (en) * 1993-07-09 1995-01-27 Japan Atom Energy Res Inst Antibacterially active agent from polysaccharide by radiation treatment and production thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB978170A (en) * 1961-08-04 1964-12-16 Koninklijke Gist Spiritus Process for the preparation of water-soluble derivatives of polyene antibiotics

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 9034 Derwent Publications Ltd., London, GB; AN 90-256413 XP002025320 & JP 02 178 229 A (FUJI REBIO KK) , 11 July 1990 *
DATABASE WPI Week 9514 Derwent Publications Ltd., London, GB; AN 95-101801 XP002025319 & JP 07 025 772 A (JAPAN ATOMIC ENERGY RES INST) , 27 January 1995 *
GENERAL PHARMACOLOGY, vol. 21, no. 2, 1990, pages 175-9, XP000617609 IKEDA, T. ET AL: "Low cariogenicity of the tetrasaccharide Nystose" *
JOURNAL OF CARBOHYDRATE CHEMISTRY, vol. 10, no. 4, 1991, page 509-22 XP000575175 HIDAKA, H. ET AL: "Fructooligosaccharides enzymatic preparation and biofunctions" cited in the application *
JOURNAL OF DENTAL RESEARCH, vol. 63, no. 11, 1984, pages 1293-97, XP000617603 IMAI, S. ET AL: "Screening of sugars inhibitory against sucrose-dependent synthesis and adherence of insoluble glucan and acid production by streptococcus mutans" *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0951844A2 (en) * 1998-04-22 1999-10-27 Hans-Günter Berner Energy-drink based on fruit juices
EP0951844A3 (en) * 1998-04-22 2000-05-24 Hans-Günter Berner Energy-drink based on fruit juices
WO2000030477A1 (en) * 1998-11-19 2000-06-02 Norbert Fuchs Beverage for increasing the body's capacity to break down alcohol
US6514544B2 (en) 1998-11-19 2003-02-04 Jhs-Privatstiftung Beverage for increasing the body's capacity to break down alcohol and method thereof
WO2001060346A2 (en) * 2000-02-17 2001-08-23 Wyeth Nutritional formulation containing prebiotic substances
WO2001060346A3 (en) * 2000-02-17 2002-01-17 American Home Prod Nutritional formulation containing prebiotic substances
JP2003522784A (en) * 2000-02-17 2003-07-29 ワイス Nutritional formulations containing prebiotic substances
US6630452B2 (en) 2000-02-17 2003-10-07 Wyeth Nutritional formulation containing prebiotic substances

Also Published As

Publication number Publication date
DE69624243T2 (en) 2003-07-03
EP0837686B1 (en) 2002-10-09
IL122735A0 (en) 1998-08-16
DK0837686T3 (en) 2003-02-10
ATE225662T1 (en) 2002-10-15
ES2186788T3 (en) 2003-05-16
CA2226420A1 (en) 1997-01-30
AR002771A1 (en) 1998-04-29
NZ312022A (en) 2000-06-23
JP2002502357A (en) 2002-01-22
BR9609619A (en) 1999-04-06
US5849324A (en) 1998-12-15
NO980071D0 (en) 1998-01-07
EP0837686A2 (en) 1998-04-29
PT837686E (en) 2003-02-28
NO980071L (en) 1998-01-07
DE69624243D1 (en) 2002-11-14
AU719547B2 (en) 2000-05-11
AU6345296A (en) 1997-02-10
WO1997002830A3 (en) 1997-04-10
MX9800331A (en) 1998-07-31

Similar Documents

Publication Publication Date Title
US5827526A (en) Use of indigestible oligosaccharides to prevent gastrointestinal infections and reduce duration of diarrhea in humans
US6630452B2 (en) Nutritional formulation containing prebiotic substances
EP1255449B1 (en) Nutritional formulation containing prebiotic substances
EP0837686B1 (en) Use of indigestible oligosaccharides to treat and prevent otitis media in humans
AU766429B2 (en) Carbohydrates mixture
EP1355542B2 (en) Nutritional composition with health promoting action containing oligosaccharides
CA2499665C (en) Use of carbohydrates and compositions thereof for the treatment or prevention of diseases caused by imbalanced colon fermentation
EP1254664A2 (en) Enteral products containing indigestible oligosaccharides for treating and preventing otitis media in humans

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU BR CA IL JP MX NO NZ

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 312022

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2226420

Country of ref document: CA

Ref document number: 2226420

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/A/1998/000331

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1996922652

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996922652

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1996922652

Country of ref document: EP